Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites

Summary1.In rat brain cortex slices preincubated with [3H]5-HT, the potencies of 17 5-HT receptor agonists to inhibit the electrically evoked3H overflow and the affinities of 13 antagonists (including several β-adrenoceptor blocking agents) to antagonize competitively the inhibitory effect of unlabelled 5-HT on evoked3H overflow were determined.2.The affinities of the compounds for 5-HT1B and 5-HT2 binding sites in rat brain cortex membranes (labelled by [125I]cyanopindolol = [125I]-CYP in the presence of 30 μmol/l isoprenaline and [3H]ketanserin, respectively), for 5-HT1A binding sites in pig and rat brain cortex membranes (labelled by [3H]8-hydroxy-2-(di-n-propylamino)tetralin = [3H]8-OH-DPAT) and for 5-HT1C binding sites in pig choroid plexus membranes (labelled by [3H]mesulergine) were also determined. The affinities of the drugs for the various 5-HT recognition sites ranged over 4–5 log units (the functional experiments revealed the same range of differences between the drugs).3.There were no significant correlations between the affinities of the drugs at 5-HT1C and 5-HT2 binding sites and their potencies or affinities, determined for the 5-HT autoreceptors. In contrast, significant correlations were found between the potencies or affinities of the drugs for the autoreceptors and their affinities at 5-HT1A or 5-HT1B binding sites; the best correlations were obtained with the 5-HT1B binding site.4.Some of the drugs investigated were not included in the correlation since their agonistic or antagonistic effects on the autoreceptors were weak and pEC30 or apparent pA2 values could not be determined (<5.5). Among these drugs, 8-OH-DPAT, TVX Q 7821 (2-(4-(4-(2-pyrimidin-yl)-1-piperazinyl)-butyl)-1,2-benzisothiazol-3(2H)one-1,1-dioxide) and spiperone showed a very low affinity for 5-HT1B binding sites (pKD<5.3), but a high affinity for 5-HT1A binding sites (pKD>7.2).5.In conclusion, the evidence indicates that the presynaptic 5-HT autoreceptor belongs to the 5-HT1B receptor subtype.